María Hernández Mesa

• Mesa, María; Garcia, Guadalupe & McCabe, Kimberly (2025). Spine apparatus modulates Ca2+ in spines through spatial localization of sources and sinks. American Journal of Physiology. ISSN 0002-9513. 603(17), p. 4785–4816. doi: 10.1101/2023.09.22.558941. Full text in Research Archive Show summary

  Dendritic spines are small protrusions on dendrites in neurons and serve as sites of postsynaptic activity. Some of these spines contain smooth endoplasmic reticulum (SER), and sometimes an even further specialized SER known as the spine apparatus (SA). In this work we developed a stochastic spatial model to investigate the role of the SER and the SA in modulating Ca2+ dynamics. Using this model, we investigated how ryanodine receptor (RyR) localization, IP3R localization, spine membrane geometry and SER geometry can impact Ca2+ transients in the spine and in the dendrite. Our simulations found that RyR opening is dependent on its location in the SER and on the SER geometry. To maximize Ca2+ in the dendrites (for activating clusters of spines and spine-to-spine communication), a laminar SA was favourable with RyRs localized in the neck region, closer to the dendrite. Furthermore locating the IP3Rs in the dendrite, as measured experimentally, also increases Ca2+ in the dendrite. We also found that the presence of the SER without the laminar structure, coupled with RyR localization at the head, leads to higher Ca2+ presence in the spine. These predictions serve as design principles for understanding how spines with an ER can regulate Ca2+ dynamics differently from spines without ER through a combination of geometry and receptor localization.

• McCabe, Kimberly; Mesa, María Hernández & Rangamani, Padmini (2025). Calcium dynamics in small spaces: Lessons learned from modeling in dendritic spines. Biophysical Journal. ISSN 0006-3495. 124(21), p. 3479–3488. doi: 10.1016/j.bpj.2025.09.038. Full text in Research Archive
• Mesa, María Hernández; Garcia, G. C.; Hoerndli, F. J.; McCabe, Kimberly & Rangamani, P. (2025). Spine apparatus modulates Ca²⁺in spines through spatial localization of sources and sinks. Journal of Physiology. ISSN 0022-3751. 603(17), p. 4785–4816. doi: 10.1113/JP286859. Full text in Research Archive
• Presacan, Oriana; Mesa, María Hernández; Aldea, Alexandru C.; Andresen, Siri; Outa, Amani al & Johannessen, Julie Aarmo [Show all 9 contributors for this article] (2025). Explainable AI to unveil cellular autophagy dynamics. PLOS ONE. 20(9). doi: 10.1371/journal.pone.0331045. Full text in Research Archive Show summary

  Autophagy is a fundamental intracellular renovation process vital for maintaining cellular homeostasis through the degradation and recycling of damaged components. It is implicated in numerous pathological conditions, including cancer and neurodegenerative diseases. However, its dynamic nature and complexity pose challenges for manual analysis. In this study, we present a computational pipeline that leverages advanced deep learning models to automate the analysis of autophagic processes in 6,240 fluorescence microscopy images from the CELLULAR dataset. Our framework integrates object detection, cell segmentation, classification by autophagic state, cellular tracking, and explainability methods for interpretability. We achieved optimal results using YOLOv8 for object detection with a mAP50 of 0.80, U-Net++ for segmentation with an IoU of 0.82, and a vision transformer for classification with an accuracy of 0.86. To track cells, we developed a custom algorithm capable of handling complex scenarios such as cell division and morphological changes, all without requiring annotated tracking data. To enhance transparency, we employed explainability techniques based on class activation mappings to analyze model decision-making processes and validate classification outcomes, complemented by t-SNE visualizations for deeper insights into the data. Collaboration with biology experts validated our findings, highlighting the pipeline’s potential to advance autophagy research. This study demonstrates the potential of deep learning and explainable AI to streamline biomedical research, reduce manual effort, and uncover key autophagy dynamics.

• Mesa, María Hernández; McCabe, Kimberly & Rangamani, Padmini (2025). Synaptic cleft geometry modulates NMDAR opening probability by tuning neurotransmitter residence time. Biophysical Journal. ISSN 0006-3495. 124(7), p. 1058–1072. doi: 10.1016/j.bpj.2025.01.019. Full text in Research Archive Show summary

  Synaptic morphology plays a critical role in modulating the dynamics of neurotransmitter diffusion and receptor activation in interneuron communication. Central physical aspects of synaptic geometry, such as the curvature of the synaptic cleft, the distance between the presynaptic and postsynaptic membranes, and the surface-area-to-volume ratio of the cleft, crucially influence glutamate diffusion and N-methyl-D-aspartate receptor (NMDAR) opening probabilities. In this study, we developed a stochastic model for receptor activation using realistic synaptic geometries. Our simulations revealed substantial variability in NMDAR activation, showing a significant impact of synaptic structure on receptor activation. Next, we designed a theoretical study with idealized cleft geometries to understand the impact of different biophysical properties on receptor activation. Specifically, we found that increasing the curvature of the synaptic membranes could compensate for reduced NMDAR activation when the synaptic cleft width was large. Additionally, nonparallel membrane configurations, such as convex presynapses or concave postsynaptic densities, maximize NMDAR activation by increasing the surface-area-to-volume ratio, thereby increasing glutamate residence time and reducing glutamate escape. Furthermore, clustering NMDARs within the postsynaptic density significantly increased receptor activation across different geometric conditions and mitigated the effects of synaptic morphology on NMDAR opening probabilities. These findings highlight the complex interplay between synaptic geometry and receptor dynamics and provide important insights into how structural modifications can influence synaptic efficacy and plasticity. By considering the major physical factors that affect neurotransmitter diffusion and receptor activation, our work offers a comprehensive understanding of how variations in synaptic geometry may regulate neurotransmission.

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